The prevalence of obesity and the metabolic syndrome has reached epidemic proportions in developed countries and conveys an increased risk of diabetes and cardiovascular mortality. Even before the development of overt diabetes, individuals with the metabolic syndrome are more likely to die of cardiovascular disease. While conventional risk factors for atherosclerosis play an important role in the pathogenesis of cardiovascular disease in the metabolic syndrome, increased glucose, insulin, inflammatory cytokines, and growth factors; increased activity of the renin-angiotensin-aldosterone system; and endothelial dysfunction all lead to impaired fibrinolytic function in the metabolic syndrome. Interruption of the renin-angiotensin-aldosterone system improves fibrinolytic balance, decreases the incidence of type 2 diabetes in both animal models and clinical trials, and prevents cardiovascular events in individuals with the metabolic syndrome. Recent clinical trial data suggest that administration of a nitric oxide donor also reduces cardiovascular mortality when given on a background of drugs that interrupt the renin-angiotensin- aldosterone system. The current proposal derives from data from our laboratory and others that indicate that endogenous nitric oxide contributes to the favorable effects of angiotensin-converting enzyme (ACE) inhibition on fibrinolytic balance and insulin sensitivity through guanosine 3',5'-cyclic monophosphate (cGMP)-dependent mechanism(s), whereas nitric oxide appears to modulate stimulated exocytosis from endothelial cells through a cGMP-independent mechanism. At the same time, both ACE inhibition and pharmacologic maneuvers to increase cGMP improve insulin sensitivity and muscle glucose uptake in animal models. Based on these data we propose to test the central hypothesis that increasing cGMP, either by increasing its formation by administering a pharmacologic nitric oxide donor (SPECIFIC AIMS 1 and 3) or by preventing its degradation by administering a phosphodiesterase inhibitor (SPECIFIC AIMS 2 and 3) will enhance the favorable effects of ACE inhibition on fibrinolytic balance (primary hypothesis) and insulin sensitivity (secondary hypothesis) in individuals with the metabolic syndrome. These studies promise to yield novel pharmacological strategies to decrease the prevalence of diabetes and mortality due to thrombotic cardiovascular events in the metabolic syndrome. [unreadable] [unreadable] [unreadable]